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11 results on '"Papangelis, V"'

1. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan

Author

Vennin, C, Melenec, P, Rouet, R, Nobis, M, Cazet, As, Murphy, Kj, Herrmann, D, Reed, Da, Lucas, Mc, Warren, Sc, Elgundi, Z, Pinese, M, Kalna, G, Roden, D, Samuel, M, Zaratzian, A, Grey, St, Da Silva, A, Leung, W, Mathivanan, S, Wang, Yx, Braithwaite, Aw, Christ, D, Benda, A, Parkin, A, Phillips, Pa, Whitelock, Jm, Gill, Aj, Sansom, Oj, Croucher, Dr, Parker, Bl, Pajic, M, Morton, Jp, Cox, Tr, Timpson, P, Johns, Al, Chantrill, La, Chou, A, Steinmann, A, Arshi, M, Dwarte, T, Froio, D, Pereira, B, Ritchie, S, Chambers, Cr, Metcalf, X, Waddell, N, Pearson, Jv, Patch, Am, Nones, K, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Leonard, C, Wood, S, Grimmond, Sm, Hofmann, O, Christ, A, Bruxner, T, Samra, Js, Pavlakis, N, High, Ha, Asghari, R, Merrett, Nd, Pavey, D, Das, A, Cosman, Ph, Ismail, K, O'Connnor, C, Stoita, A, Williams, D, Spigellman, A, Lam, Vw, Mcleod, D, Kirk, J, Kench, Jg, Grimison, P, Cooper, Cl, Sandroussi, C, Goodwin, A, Mead, Rs, Tucker, K, Andrews, L, Texler, M, Forest, C, Epari, Kp, Ballal, M, Fletcher, Dr, Mukhedkar, S, Zeps, N, Beilin, M, Feeney, K, Nguyen, Nq, Ruszkiewicz, Ar, Worthley, C, Chen, J, Brooke-Smith, Me, Papangelis, V, Clouston, Ad, Barbour, Ap, O'Rourke, Tj, Fawcett, Jw, Slater, K, Hatzifotis, M, Hodgkinson, P, Nikfarjam, M, Eshleman, Jr, Hruban, Rh, Wolfgang, Cl, Lawlor, Rt, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Biankin, Av, Dixon, J, Jamieson, Nb, and Chang, Dk

Subjects
0301 basic medicine, medicine.medical_treatment, Drug Resistance, General Physics and Astronomy, 02 engineering and technology, Mice, Cancer-Associated Fibroblasts, Cell Movement, lcsh:Science, Inbred BALB C, Cancer, education.field_of_study, Mice, Inbred BALB C, Multidisciplinary, Tumor, 021001 nanoscience & nanotechnology, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, 0210 nano-technology, Pancreas, Signal Transduction, Cancer microenvironment, Cell biology, Science, Population, Perlecan, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, Pancreatic cancer, Cell Line, Tumor, medicine, Humans, Animals, Neoplasm Invasiveness, education, Cell Proliferation, Neoplastic, fungi, General Chemistry, Immunotherapy, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Gene Expression Regulation, Drug Resistance, Neoplasm, Cancer cell, Cancer research, biology.protein, Neoplasm, lcsh:Q, Stromal Cells, Tumor Suppressor Protein p53, Heparan Sulfate Proteoglycans
Abstract

Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer., Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.

Published
2019

2. DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Author

Lakis, V, Lawlor, RT, Newell, F, Patch, AM, Mafficini, A, Sadanandam, A, Koufariotis, LT, Johnston, RL, Leonard, C, Wood, S, Rusev, B, Corbo, V, Luchini, C, Cingarlini, S, Landoni, L, Salvia, R, Milella, M, Chang, D, Bailey, P, Jamieson, NB, Duthie, F, Gingras, MC, Muzny, DM, Wheeler, DA, Gibbs, RA, Milione, M, Chantrill, LA, Timpson, P, Chou, A, Pajic, M, Murphy, A, Dwarte, T, Hermann, D, Vennin, C, Cox, TR, Pereira, B, Ritchie, S, Reed, DA, Chambers, CR, Metcalf, X, Nobis, M, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Xu, Q, Hofmann, O, Samra, JS, Pavlakis, N, Arena, J, High, HA, Asghari, R, Merrett, ND, Pavey, D, Das, A, Cosman, PH, Ismail, K, O’Connnor, C, Stoita, A, Williams, D, Spigellman, A, Lam, VW, McLeod, D, Kirk, J, Kench, JG, Grimison, P, Sandroussi, C, Goodwin, A, Mead, RS, Tucker, K, Andrews, L, Texler, M, Forest, C, Ballal, M, Fletcher, DR, Zeps, N, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Chen, J, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Barbour, AP, O’Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Nikfarjam, M, Eshleman, JR, Hruban, RH, Wolfgang, CL, Dixon, J, Scardoni, M, Bassi, C, Grimaldi, S, Cantù, C, Bonizzato, G, Bersani, S, Lakis, V, Lawlor, RT, Newell, F, Patch, AM, Mafficini, A, Sadanandam, A, Koufariotis, LT, Johnston, RL, Leonard, C, Wood, S, Rusev, B, Corbo, V, Luchini, C, Cingarlini, S, Landoni, L, Salvia, R, Milella, M, Chang, D, Bailey, P, Jamieson, NB, Duthie, F, Gingras, MC, Muzny, DM, Wheeler, DA, Gibbs, RA, Milione, M, Chantrill, LA, Timpson, P, Chou, A, Pajic, M, Murphy, A, Dwarte, T, Hermann, D, Vennin, C, Cox, TR, Pereira, B, Ritchie, S, Reed, DA, Chambers, CR, Metcalf, X, Nobis, M, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Xu, Q, Hofmann, O, Samra, JS, Pavlakis, N, Arena, J, High, HA, Asghari, R, Merrett, ND, Pavey, D, Das, A, Cosman, PH, Ismail, K, O’Connnor, C, Stoita, A, Williams, D, Spigellman, A, Lam, VW, McLeod, D, Kirk, J, Kench, JG, Grimison, P, Sandroussi, C, Goodwin, A, Mead, RS, Tucker, K, Andrews, L, Texler, M, Forest, C, Ballal, M, Fletcher, DR, Zeps, N, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Chen, J, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Barbour, AP, O’Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Nikfarjam, M, Eshleman, JR, Hruban, RH, Wolfgang, CL, Dixon, J, Scardoni, M, Bassi, C, Grimaldi, S, Cantù, C, Bonizzato, G, and Bersani, S

Abstract

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

Published
2021

7. Lost in translation: Returning germline genetic results in genome-scale cancer research

Author

Johns, AL, McKay, SH, Humphris, JL, Pinese, M, Chantrill, LA, Mead, RS, Tucker, K, Andrews, L, Goodwin, A, Leonard, C, High, HA, Nones, K, Waddell, N, Patch, AM, Merrett, ND, Pavlakis, N, Kassahn, KS, Samra, JS, Miller, DK, Chang, DK, Pajic, M, Pearson, JV, Grimmond, SM, Zeps, N, Gill, AJ, Biankin, AV, Chin, VT, Chou, A, Steinmann, A, Arshi, M, Drury, A, Froio, D, Morgan, A, Timpson, P, Hermann, D, Vennin, C, Warren, S, Wu, J, Pinho, AV, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Wood, S, Xu, C, Hofmann, O, Wilson, PJ, Christ, A, Bruxner, T, Samra, S, Arena, J, Mittal, A, Asghari, R, Pavey, D, Das, A, Cosman, PH, Ismail, K, O'Connnor, C, Williams, D, Spigellman, A, Lam, W, McLeod, D, Nagrial, AM, Kirk, J, James, V, Grimison, P, Cooper, CL, Sandroussi, C, Forest, C, Epari, KP, Ballal, M, Fletcher, DR, Mukhedkar, S, Beilin, M, Feeney, K, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Martin, P, Barbour, AP, O'Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Hruban, RH, Wolfgang, CL, Hodgin, M, Lawlor, RT, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Bailey, P, Martin, S, Musgrove, EA, Johns, AL, McKay, SH, Humphris, JL, Pinese, M, Chantrill, LA, Mead, RS, Tucker, K, Andrews, L, Goodwin, A, Leonard, C, High, HA, Nones, K, Waddell, N, Patch, AM, Merrett, ND, Pavlakis, N, Kassahn, KS, Samra, JS, Miller, DK, Chang, DK, Pajic, M, Pearson, JV, Grimmond, SM, Zeps, N, Gill, AJ, Biankin, AV, Chin, VT, Chou, A, Steinmann, A, Arshi, M, Drury, A, Froio, D, Morgan, A, Timpson, P, Hermann, D, Vennin, C, Warren, S, Wu, J, Pinho, AV, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Wood, S, Xu, C, Hofmann, O, Wilson, PJ, Christ, A, Bruxner, T, Samra, S, Arena, J, Mittal, A, Asghari, R, Pavey, D, Das, A, Cosman, PH, Ismail, K, O'Connnor, C, Williams, D, Spigellman, A, Lam, W, McLeod, D, Nagrial, AM, Kirk, J, James, V, Grimison, P, Cooper, CL, Sandroussi, C, Forest, C, Epari, KP, Ballal, M, Fletcher, DR, Mukhedkar, S, Beilin, M, Feeney, K, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Martin, P, Barbour, AP, O'Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Hruban, RH, Wolfgang, CL, Hodgin, M, Lawlor, RT, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Bailey, P, Martin, S, and Musgrove, EA

Abstract

Background: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. Methods: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. Results: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. Conclusion: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning

Published
2017

8. RON is not a prognostic marker for resectable pancreatic cancer

Author

Tactacan, Carole M, Chang, David K, Cowley, Mark J, Humphrey, Emily S, Jianmin, Wu, Gill, Anthony J, Chou, Angela, Nones, Katia, Grimmond, Sean M, Sutherland, Robert L, Biankin, Andrew V, Daly, Roger J, Biankin, Av, Johns, Al, Mawson, A, Chang, Dk, Scarlett, Cj, Brancato, Ma, Rowe, Sj, Simpson, Sl, Martyn-Smith, M, Chantrill, La, Chin, Vt, Chou, A, Cowley, Mj, Caplan, W, Humphris, Jl, Jones, Md, Mead, R, Nagrial, Am, Pajic, M, Pettit, J, Pinese, M, Rooman, I, Wu, Jun, Daly, Rj, Musgrove, Ea, Sutherland, Rl, Grimmond, Sm, Waddell, N, Kassahn, Ks, Miller, Dk, Wilson, Pj, Patch, Am, Song, S, Harliwong, I, Idrisoglu, S, Nourse, C, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Anderson, Michela, Holmes, O, Leonard, C, Taylor, D, Wood, JOHN STEPHAN, Xu, C, Nones, K, Fink, Julika, Christ, A, Bruxner, T, Cloonan, N, Newell, F, Pearson, Jv, Samra, Js, Gill, Aj, Nickpavlakis, Guminski, A, Toon, C, Asghari, R, Merrett, Nd, Pavey, Da, Das, A, Cosman, Ph, Ismail, K, O'Connor, C, Lam, Vw, Mcleod, D, Pleass, Hc, James, V, Kench, Jg, Cooper, Cl, Joseph, D, Sandroussi, C, Crawford, M, Texler, M, Forrest, C, Laycock, A, Epari, Kp, Ballal, M, Fletcher, Dr, Mukhedkar, S, Spry, Na, Deboer, B, Chai, M, Feeney, K, Zeps, N, Beilin, M, Nguyen, Nq, Ruszkiewicz, Ar, Worthley, C, Tan, Cp, Debrencini, T, Chen, J, Brooke-Smith, Me, Papangelis, V, Tang, H, Barbour, Ap, Clouston, Ad, Martin, P, O'Rourke, Tj, Chiang, A, Fawcett, Jw, Slater, K, Yeung, S, Hatzifotis, M, Hodgkinson, P, Christophi, C, Nikfarjam, M, Eshleman, Jr, Hruban, Rh, Maitra, A, Iacobuzio-Donahue, Ca, Schulick, Rd, Wolfgang, Cl, Morgan, Ra, Scarpa, A, Lawlor, Rt, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Tempero, Ma., and Basic (bio-) Medical Sciences

Subjects
Oncology, Male, Receptor Protein-Tyrosine Kinases/analysis, Cancer Research, Receptor tyrosine kinase, Kaplan-Meier Estimate, Surgical oncology, 80 and over, Prospective cohort study, Pancreatic Neoplasms/metabolism, Biomarker, Gemcitabine, Chemotherapy, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Blotting, Western, Female, Humans, Immunohistochemistry, Middle Aged, Pancreatic Neoplasms, Prognosis, Proportional Hazards Models, Receptor Protein-Tyrosine Kinases, Tissue Array Analysis, Tumor, Blotting, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Adenocarcinoma/metabolism, CA19-9, Western, Research Article, medicine.drug, medicine.medical_specialty, lcsh:RC254-282, Biomarkers, Tumor/analysis, Breast cancer, Internal medicine, Pancreatic cancer, medicine, Genetics, business.industry, Cancer, medicine.disease, business, aged, 80 and over, Biomarkers
Abstract

Background The receptor tyrosine kinase RON exhibits increased expression during pancreatic cancer progression and promotes migration, invasion and gemcitabine resistance of pancreatic cancer cells in experimental models. However, the prognostic significance of RON expression in pancreatic cancer is unknown. Methods RON expression was characterized in several large cohorts, including a prospective study, totaling 492 pancreatic cancer patients and relationships with patient outcome and clinico-pathologic variables were assessed. Results RON expression was associated with outcome in a training set, but this was not recapitulated in the validation set, nor was there any association with therapeutic responsiveness in the validation set or the prospective study. Conclusions Although RON is implicated in pancreatic cancer progression in experimental models, and may constitute a therapeutic target, RON expression is not associated with prognosis or therapeutic responsiveness in resected pancreatic cancer.

Published
2012

9. Returning individual research results for genome sequences of pancreatic cancer

Author

Johns, A., Miller, D., Simpson, S., Gill, A., Kassahn, K., Humphris, J., Samra, J., Tucker, K., Andrews, L., Chang, D., Waddell, N., Pajic, M., Pearson, J., Grimmond, S., Biankin, A., Zeps, Nikolajs, Martyn-Smith, M., Tang, H., Papangelis, V., Beilin, M., Johns, A., Miller, D., Simpson, S., Gill, A., Kassahn, K., Humphris, J., Samra, J., Tucker, K., Andrews, L., Chang, D., Waddell, N., Pajic, M., Pearson, J., Grimmond, S., Biankin, A., Zeps, Nikolajs, Martyn-Smith, M., Tang, H., Papangelis, V., and Beilin, M.

Abstract

Background: Disclosure of individual results to participants in genomic research is a complex and contentious issue. There are many existing commentaries and opinion pieces on the topic, but little empirical data concerning actual cases describing how individual results have been returned. Thus, the real life risks and benefits of disclosing individual research results to participants are rarely if ever presented as part of this debate. Methods: The Australian Pancreatic Cancer Genome Initiative (APGI) is an Australian contribution to the International Cancer Genome Consortium (ICGC) that involves prospective sequencing of tumor and normal genomes of study participants with pancreatic cancer in Australia. We present three examples that illustrate different facets of how research results may arise, and how they may be returned to individuals within an ethically defensible and clinically practical framework. This framework includes the necessary elements identified by others including consent, determination of the significance of results and which to return, delineation of the responsibility for communication and the clinical pathway for managing the consequences of returning results.Results: Of 285 recruited patients, we returned results to a total of 25 with no adverse events to date. These included four that were classified as medically actionable, nine as clinically significant and eight that were returned at the request of the treating clinician. Case studies presented depict instances where research results impacted on cancer susceptibility, current treatment and diagnosis, and illustrate key practical challenges of developing an effective framework. Conclusions: We suggest that return of individual results is both feasible and ethically defensible but only within the context of a robust framework that involves a close relationship between researchers and clinicians.

Published
2014

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